Ephrin receptor A2 (EphA2) is a member of the
Ephrin/
Eph receptor cell-to-cell signaling family of molecules, and it plays a key role in cell proliferation, differentiation, and migration. EphA2 is overexpressed in a broad range of
cancers, and its expression is in many cases associated with poor prognosis. We recently developed a novel EphA2-targeting antibody-directed nanotherapeutic encapsulating a labile
prodrug of
docetaxel (EphA2-ILs-DTXp) for the treatment of EphA2-expressing
malignancies. Here, we characterized the expression of EphA2 in
bladder cancer using immunohistochemistry in 177 human
bladder cancer samples and determined the preclinical efficacy of EphA2-ILs-DTXp in four EphA2-positive patient-derived xenograft (PDX) models of the disease, either as a monotherapy, or in combination with
gemcitabine. EphA2 expression was detected in 80-100% of
bladder cancer samples and correlated with shorter patient survival. EphA2 was found to be expressed in
tumor cells and/or
tumor-associated blood vessels in both primary and metastatic lesions with a concordance rate of approximately 90%. The EphA2-targeted antibody-directed nanotherapeutic EphA2-ILs-DTXp controlled
tumor growth, mediated greater regression, and was more active than free
docetaxel at equitoxic dosing in all four EphA2-positive
bladder cancer PDX models. Combination of EphA2-ILs-DTXp and
gemcitabine in one PDX model led to improved
tumor growth control compared to monotherapies or the combination of free
docetaxel and
gemcitabine. These data demonstrating the prevalence of EphA2 in
bladder cancers and efficacy of EphA2-ILs-DTXp in PDX models support the clinical exploration of EphA2 targeting in
bladder cancer.